Tetrahydrodibenzopyrans

ABSTRACT

(-)-1-Hydroxy-3-alkyl-6,6-dimethyl-9-hydroxymethyl-6a,10a-trans6a,7,10,10a -tetrahydrodibenzo-(b,d)-pyrans (Formula 1) are produced in good yields from the corresponding 9-methylene-1,8di-acyl compounds (Formula 2) by thermal conversion of the latter into the corresponding 1,11-di-acyl compounds (Formula 3) which are converted into the target compound (Formula 1) by removal of the two acyl groups. Formula 1 compounds, where the alkyl group is a straight or branched chain alkyl of from 1-4 and 6-10 Catoms are novel homologues of the 3-n-pentyl compound, a metabolite of tetrahydrocannabinol known per se. Formula 1 compounds have bactericidic, sedative, analgetic and psychomimetic effect when applied to the human organism. Novel compounds (Formulae 4a, 5b, 6 and 7) are disclosed as starting materials and/or intermediates, some of them having pharmacological utility similar to the Formula 1 compounds.

United stateS Patent [191 Petrzilka 111 3,873,576 Mar. 25, 1975 l l TETRAHYDRODIBENZOPYRANS [76] Inventor: Theodor Petrzilka, Rigistrasse 6,

8703 Erlenbach, Switzerland [22] Filed: Oct. 5, 1972 [2]] Appl. No.: 295,262

[30] Foreign Application Priority Data Oct. 14, 1971 Switzerland 14966/71 521 US. Cl. 260/345.3, 424/283 511 int. Cl c070 7/20 581 Field of Search 260/3453 [56] References Cited UNITED STATES PATENTS 3388136 6/1968 Taylor et a1. 260/3453 3,668,224 6/1972 Petrzilka 260/3453 Primary Examiner-John M. Ford Attorney, Agent, or Firm-Werner W. Kleeman.

57 v ABSTRACT (-)-l-l-lydroxy-3-alkyl-6,6-dimethyl-9-hydroxymethyl- 6a, 1 0a-trans-6a,7, l 0, l Oa-tetrahydrodibenzo-( b,d

pyrans (Formula 1) are produced in good yields from the corresponding 9-methylene-l,8-di-acyl compounds (Formula 2) by thermal conversion of the latter into the corresponding 1,1l-'di-acyl compounds (Formula 3) which are converted into the target compound (Formula 1) by removal of the two acyl groups. Formula 1 compounds, where the alkyl group is a straight or branched chain alkyl of from 14 and 6-10 C- atoms are novel homologues of the 3-n-pentyl compound, a metabolite of tetrahydrocannabinol known per se. Formula 1 compounds have bactericidic, sedative, analgetic and psychomimetic effect when applied to the human organism. Novel compounds'(Formulae 4a, 5b, 6 and 7) are disclosed as starting materials and/or intermediates, some of them having pharmacological utility similar to the Formula 1 compounds.

12 Claims, 16 Drawing Figures 1 TETRAHYDRODIBENZOPYRANS BACKGROUND OF THE INVENTION tered in vivo to rabbits or contacted in vitro with liver.

homogenate are converted into derivatives generally called metabolites of THC, i.e. tetrahydrocannabinol. Among the metabolites, the ll-hydroxy metabolite (also referred to herein as the 9-hydroxymethyl metabolite) proved to be several times more active than THC itself. In view of the pharmacological potential of THC and some of its derivatives and the extremely small yields of metabolite production in vivo or in vitro a process of synthesizing such active metabolites in good yields was required. Previous attempts to achieve such synthesis failed, apparently due to the complex and stereo-specific structure of this type of compounds.

It is one of the main objects of this invention to provide a process for producing such metabolites as well as their 3-alkyl homologues.

Another object is to provide for novel starting substances and intermediates for such synthesis.

Other objects will become apparent as the specification proceeds.

SUMMARY OF INVENTION In accordance with the above and further objects, I have found that compounds of Formula 1 in which R is a straight or branched chain alkyl group including from 1 to about 10 carbon atoms (all compound formulae being given in the attached Formula Sheet) including the l l-hydroxy metabolite of THC known per se, as well as certain 3-alkyl homologues can be obtained in good yields, say in the order of at least 50 of the theoretical yield, from the corresponding 9-methylenel,8-di-acyl compound of Formula 2 in which R is hydrogen or a lower alkyl group, preferably methyl, including from 1 through carbon atoms, by thermal conversion of a Formula 2 compound thus yielding the bis-acyl compound of Formula 3, in which R and R, are as above, which is then converted into the target compound of Formula I by removing both acyl groups. The desired Formula 1 compounds including the known 3- n-pentyl compound mentioned above as well as the novel alkyl homologues thereof exhibit pharmacological activity as set forth below more in detail.

Preferably, thermal conversion of compound 2 into compound 3 is achieved by simply heating compound 2, e.g. at temperatures of above 200C, e.g. from about 250 to about 300C, a temperature of 290C i 10C being particularly preferred. Inert diluents need not be present during the heating step and, preferably, air is excluded during the thermal conversion of compound 2.

Removal of the two acyl groups from compound 3, Le. from the conversion product, can be achieved by methods known in the art, e.g. reduction techniques, preferably by heating compound 3 in an enert solvent and in the presence of LiAlI-I,.

Further, the invention provides; as novel substances, the compounds of Formula I in which R is straight or branched alkyl of l-lO C-atoms excluding the compound where R, is n-pentyl, and the compounds of Formulae 4a, 5b, 6 and 7 in which R is the pentyl group or another C -C alkyl group.

DETAILED DESCRIPTION OF INVENTION First, with reference to the annexed Formula Sheet and in view of different systems of nomenclature used for tetrahydrodibenzopyrans, Formula 1 shows the target compound and the numbering system used throughout the specification. Before proceeding tothe details of the compounds shown it is to be understood that the bonds or lines shown in 6-position of all Formulae do not represent free bonds but methyl groups 'CH each line representing one such group. By the same token, the free line in 9-position of Formulae 6, 7 and also designates a methyl group. On the other hand, the double line in 9-position of Formulae 8a, 8b and 12 designates a double bond to and including the methylene group =CH The two hydrogen atoms in 6a and 10a are sterically arranged such that the hydrogen at the end of the full line in 6a-position is above the plane of drawing while the hydrogen attheend of the broken line in IOa-position is below the plane of drawing.

The undulated lines shown as bonding signs for specific groups in Formulae 2, 6, 7, 8c and 12 indicate that the group thus defined can be in one of two diastereomeric forms, i. e. below or above the plane of drawing. Such Formulae are intended to include either diastereomer or any mixture thereof.

Similarly, the position of the substituents in the 8- orland 9-positions in Formulae 4a, 4b, 5a, 8a and 8b are marked to show diastereomers.

Group R in Formulae 2 and 3 is hydrogen or a lower alkye group of from 1 to about 5 C-atoms, R methyl being a preferred embodiment so that the preferred acyl group in positions 1 and 8 of Formula 2, and l and ll of Formula 3 is the acetyl group.

R in Formulae l-l2 is straight or branched chain alkyl, e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, etc.

R in Formulae 4a, 4b and I2 is a protective group of the type known in the art, preferably the tetrahydropyranyl group.

Also, R in Formulae 8a, 8b, 8c and l l is a protective group and can be the same as R,. A preferred protective group R is the acetyl group.

The starting substance, i. e. a Formula 2 compound, for the process of the invention may be obtained in various ways, the following methods A and B being preferred, however. Each method comprises a sequence of steps identified below as A-l to A-S and B-l to B-S:

fA-l) Formula 9 Formula l0 7 (A-2) Formula 10 Formulae 4a, 4b (A-3) Formulae 4a, 4b Formula 12 A-4) Formula 12 Formulae 5a, 5b

acyla t ion of (A5)Forn1ulae5a,5b Formula2 H both hydroxyls (B-l) Formula 9 W8 Formula II (B-2) Formula ll MM Formulae 8a, 8b

reduction of (ll-3) Formulae 8n, sh Fmmllllltl 5a, 5b, 0 7 perhydroxy groups (B-4) Formulae 5a, 5b, 6 wFormulae 5a,

Milly;

(B-5) Formulae 5a, 5b

acylatlon of both hydroxyls Accordingly, both preferred methods A and B start from a Formula 9 compound which in turn can be ob- Formula 2 tained in good yields according to the process disclosed in my US Pat. No. 3,560,528, issued Feb. 7, l97l, incorporated by reference into the present specification.

While specific Examples for both methods A and B will be given below, these are some general remarks re garding the A and B syntheses:

Step A-l: The protective group R introduced in this step should be stable under alkaline conditions. Examples of suitable R groups are the trimethylsilyl group and the O-tetrahydropyranyl group, the latter being particularly preferred. Suitable procedures are well known per se in the art, as are other suitable groups. Product isolation is neither critical nor required.

Step A-2: Epoxydation of 10 can be effected according to methods known per se, e.g. by means of peracids such as m-chloro perbenzoic acid in inert solvents. The epoxides 4a, 4b are diastereomers and can be used singly or in mixture for the next step. Product isolation is not required.

Step A-3: Here, the epoxide ring is opened to produce a Formula 12 compound in a manner known per se in the art, e. g. by treatment with a base in an inert solvent using such bases as alkali metal alcoholates, e. g. lithium, sodium or potassium salts of methyl, ethyl, propyl, t-butyl or t-amyl alcohol, butyl lithium being the preferred base.

Step A-4: Now, the protective group will be removed in a manner known per se in the art, e. g. by treatment with a mineral acid, generally a diluted aqueous or alcoholic acid such as hydrochloric, hydrobromic or hydroiodic acid. The preferred acid is hydrochloric acid.

Suitable inert solvents in this and other steps are normally liquid hydrocarbons such as pentane, hexane, benzene, toluene, xylene or ethers, e. g. diethyl ether, benzylmethyl ether, tetrahydrofurane or dimethoxy ethane. The preferred solvent is diethyl ether. The reaction temperature is not critical; in a preferred embodiment of the reaction, the base is added at C, whereupon the temperature is allowed to rise to 35-80C.

It is to be noted that steps A-3 and A-4 can be combined into a single treatment, i. e. if group R will be removed by the reaction conditions selected to open the epoxide ring. In either case, isolation of product 511, 5b is not required, nor is separation of the diastereomers necessary or advantageous.

Step A-5: This is the acylation of both hydroxyls in 8- and l-position. Depending upon the R group required for compound 2, treatment with the corresponding acid, acid anhydride, acid chloride, etc. under conditions of esterification is quite suitable. Acetylation, e. g. with acetic anhydride in pyridine, is a preferred embodiment.

Preferably, the product of Formula 2 thus obtained is recovered and purified, but a raw product is suitable for subsequent thermal conversion explained more in detail below.

Step 8-1: The protective group R introduced in this step into compound 9 is not particularly critical and both suitable groups and suitable methods are known per se. However, acyl groups are preferred for R and his even more preferred to use such acyl groups, e. g. the acetylgroup, which carry the group R adjacent to the carbonyl group. In other words, if R in Formulae 2 and 3 is to stand for methyl, R preferably is acetyl because this will avoid the necessity of exchanging R for R in the later stages of this method. Acylation or acetylation can be effected as in step A-5. Purification of product (Formula I l) is not required.

Step B-2: Photooxydation of the Formula II compound can be effected by treatment with actinic radiation, preferably UV light, in the presence of oxygen, e. g. gaseous oxygen. As is common in the art of photooxydation, sensitizers can be used in this step, fluorescein and rose bengal being typical examples, and operation in liquid media, e. g. a solvent inert tothe irradiation, is preferred. Suitable examples of solvents include normally liquid hydrocarbons such as pentane, hexane, benzene, toluene, xylene and/or alcohols'such as methanol, ethanol, propanol, n and t butanol and n and t amyl alcohol. A preferred solvent is a 1:1 mixture of benzene/methanol.

The product of this step is a mixture of 8a, 8b 'compound with the peroxy-precursor of the compound of Formula (i.e. where the hydroxyl in 9-position is a peroxy group). Preferably, this mixture is used directly as the starting material for the subsequent step B-3, and in practice the entire reaction mixture can be used for conducting step B-3.

. Step 8-3: This involves reduction of the perhydroxy group formed in step 8-2 which is another technique well known per se.

Numerous reduction techniques will also cause removal of the protective group R in this step. This, in fact, is preferred. If the reduction method used will not remove group R an additional step to effect this will be required, unless this group does already constitute the desired substituent for the l-position of compound 2, e.g. if R is to be methyl and R is acetyl.

In either case, the result of this step is a mixture of diastereometric compound 5a, 5b (with either free hydroxyl in l-position or still carrying group R on the oxygen in l-position) together with compound of Formula 6 which is a side product of this method but also an interesting new chemical species as explained below.

A preferred reduction technique for step 8-3 is treatment with sodium borohydride, e.g. in methanol. Reductions of this type yield the free l-phenols of Formulae 5a, 5b and 6 directly.

Step B-4: This involves separation of the combined diastereomers 5a, 51) from compound 6, both for the purposes of improving the yields in the subsequent use of 5a, 5b toward production of compound I as well as for recovering the valuable side-product of Formula 6. Simple distillation and/or chromatography techniques are suitable for this purpose.

Step B-51 The diastereomers recovered in step B-4 (i.e. Formulae 5a, 5b compounds) are acylated to produce the desired Formula 2 compound. This step is the same as A-5.

As noted above, compounds of Formula 6 are a novel species. They are obtained according to step l-3 of the above method B and isolated as a product from step 8-4. In general, they exhibit valuable pharmacological properties of the type disclosed herein for Formula 1 compounds. In addition, they can be converted into another novel species, i.e. compounds of Formula 7, by conventional catalytic hydrogenation methods. The novel Formula 7 compounds exhibit pharmacological utility of the type disclosed for Formula 1 compounds.

Turning now to the conversion of Formula 2 compounds into Formula 3 compounds (the latter being then converted into the subject target compound of Formula 1), it has been mentioned above that this conversion can be simply achieved by heating of compound 2. The mechanism of the rearrangement involved has not been fully established but it is surprising indeed that conversion of compound 2 into compound 3 can be achieved by mere heating in good yields, considering the complexity and steric specifity of the molecular structures involved.

Presence of a liquid inert phase is not necessary for the thermal conversion and is not even preferred. If a liquid inert phase or diluent is to be used, common inert solvents such as benzene, toluene, xylene, biphenyl ether, etc. are suitable. When such liquids are used for the thermal conversion of compound 2, apparatus means suitable for withstanding the autogenic pressure of the mixture at conversion temperatures of above 200C will have to be used.

According to a preferred way of effecting thermal conversion, the Formula 2 compound is heated without additives to a temperature of from about 200 to about 300C, preferably 250-300C, and most preferred to about 290C (i C). Heating under vacuum, e.g. 0.001 torr, is preferred, for example by introducing Formula 2 compound into a suitable recipient, evacuation of air therefrom, and sealing the recipient, e. g. a heavy glass tube.

The reaction time can be varied between about 1-60 minutes with higher temperatures requiring shorter re action times, and vice-versa. At about 290C a reaction time of about minutes is preferred and renders yields of Formula 3 compound in the order of about 60 7c by weight.

Removal of the acyl groups in 1- and ll-position of Formula 3 yields the target compound of Formula 1. Suitable techniques for removing acyl groups such as to leave the hydroxyl group instead of the acyl are well known per se, e.g. reduction or hydrolysis. The reduction technique in an inert liquid medium is preferred here for practical reasons (product purity), e.g. using lithium aluminium hydride (LiAlH,) as reduction agent and an inert solvent, e.g. tetrahydrofuran, dimethoxyethane. diethyl ether, etc. the last named solvent being preferred for ease of subsequent removal and product recovery.

The product thus obtained can be purified in a manner known per se, e.g. chromatography.

As mentioned above, compounds of formula 1 are useful as psychomimetic agents, sedatives and analgesics. They can be formulated as novel pharmaceutical preparations together with conventional pharmaceutical organic or inorganic carrier materials suitable for internal administration. Pharmaceutical Formula compositions containing the compounds of Formula 1 can be administered parenterally or orally, the dosages to be adjusted according to individual requirements. For example, these compounds can be adminstered in dosages of from about 0.1 mg/kg to about 5 mg/kg per day, either in a single or in a repeated divided dosage. The novel pharamceutical compositions can contain such conventional organic or inorganic inert carrier materials as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols,

vaselinc or the like. The pharmaceutical preparations can be in the conventional solid forms such as tablets, dragees, suppositories, capsules or in conventional liquid form such as solutions, suspensions of emulsions. The pharmaceutical compositions can be submitted to conventional pharmaceutical expedients such as sterilization and/or can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers or the like. They also can contain other therapeutically useful materials.

The following Examples are illustrative but not limitative of the invention. Percentages are by weight unless indicated otherwise.

EXAMPLE 1 Preparation of (-)-1-O-tetrahydropyraryl-3-n-pentyl-6,6,9-trimethyl- 6a,10-trans-6a,7,l0,10a-tetrahydrodibenzo-(b,d)- pyran (Formula 10):

3.14 of Formula 9 compound (R n-pentyl) are added dropwise to a solution of 4.20 g 3,4-dihydro-2H- pyran (commercial grade) in 20 ml of methylene chloride containing 20 mg of p-toluene sulfonic acid. The mixture is stirred for 1 hour at room temperature. After addition of ethyl ether, the resulting solution is extracted with 2 n sodium hydroxide solution. After drying the ether solution over sodium sulfate the ether is evaporated leaving 5.0 g of an oily residue which is purifled by chromatography over g of aluminium oxide (trade product from M. Woelm Corp., Eschwege, Germany). Elution with petroleum ether yields 2.86;; of the desired Formula 10 compound (R C H R =tetrahydropyranyl) The Rf value of this compound in chloroform is 0.60, the boiling point at 0.01 torr is 195205C. (1,?" -22lC (0.36 in chloroform). Analytical data and IR, NMR and MS spectra confirm the structure given.

EXAMPLE 11 Preparation of (-)-8,9-epoxy-l-0-tetrahydropyrany1-3-n-pentyl- 6,6,9-trimethy1-6a,l0a-trans-6a,7,10,10a-tetrahydrodibenzo-(b,d)-pyran (Formulae 4a, 4b):

2.86 g of the compound obtained in Example 1 are dissolved in 20 ml of methylene chloride. Then 1.6 g of m-chloro-perbenzoic acid (commercial grade) dissolved in 30 ml of methylene chloride are added dropwise to the solution at room temperature. The resulting mixture is kept at room temperature for 15 hours. Thereafter, the excess of m-chloro-perbenzoic acid is destroyed by addition of aqueous 10 sodium sulfite solution. The organic layer obtained is washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. The crude residue is chromatographed on 60 g ofFlorisil, a commercial magnesium silicate absorbent. Elution with benzene yields 1.9 g of pure compound according to Formulae 4a, 4b, in which R is C l-l and R is tetrahydropyranyl. Analytical data as well as 1R, NMR and MS spectra confirm the structure given.

The Rf value in chloroform is 0.19. The boiling point is 170C/0.01 mml-lg.

EXAMPLE I11 Preparation of (-)-1-0-tetrahydropyrany1-3-n-penty1-8-hydroxy-6,6,9- trimethyl-9-methylidene-6a,10a-trans-6a,7,10,1021- tetrahydrodibenzo-(b,d)-pyran (Formula 12) 6 ml of a 2.5 molar solution of butyllithium in hexane are added dropwise to a solution of 1.491 g of the compound obtained according to Example II in 30 ml of dry ethyl ether at a temperature of C. When addition is complete, the temperature of the solution is allowed to rise to ambient temperature. Then, the reaction mixture is refluxed for 4 hours. After addition of ice, the organic layer obtained is washed with water and dried over sodium sulfate. After evaporation of the ether 1.436 g of a yellow oil are obtained. Chromatography over aluminium oxide (neutral grade, Woelm Corp.) and elution with methylene chloride yields 850 mg of the compound of Formula 12 (R n-pentyl, R tetrahydropyranyl). 1

Analytical data as well as IR, NMR and MS spectra confirm the structure given.

The Rf value in chloroform is 0.10. The boiling point is 210220C/0.001 mmHg.

EXAMPLE IV Preparation of (-)-l ,8-dihydroxy-3-n-pentyl-6,6-dimethyl-9- methylidene-6a,10a-trans-6a,7,10,10a-tetrahydrodibenzo-(b,d)-pyran (Formulae a, 5b)

393 mg of the compound obtained according to Example III are dissolved in 20 ml of dioxane. 4 ml of 2 n sulfuric acid are added to this solution. The resulting mixture is stirred over night at room temperature. Extraction with ether yields 411 mg of viscous yellow oil which is then chromatographed over g of Florisil (magnesium silicate). Elution with methylene chloride yields 250 mg of the compound of Formulae 5a, 512(R n-pentyl).

Analytical data as well as IR, NMR and MS spectra confirm the structure given.

The Rfvalue in chloroform/methanol 9:1 is 0.50. The boiling point is 215C/0.00l mmHg.

EXAMPLE V Preparation of (-)-1,8-bisacetoxy-3-n-pentyl-6,6-diemthyl-9- methylidene-oa,l0a-trans-6a,7,10,10a-tetrahydrodibenzo-(b,d)-pyran (Formula 2) 300 mg of the compound obtained according to Example IV are dissolved in 3 ml acetic anhydride and 3 ml of anhydrous pyridine. The resulting solution is kept under argon in a dry atmosphere for 12 hours at room temperature. After evaporation of the solvents under reduced pressure the residue is dissolved in ether and extracted with aqueous sodium bicarbonate solution. After evaporation ofthe dried ether extract the residue is distilled at 180C/0.01 mmHg.

357 of pure Formula 2 compound (R methyl, R, n-pentyl) are obtained.

Analytical data as well as IR, NMR and MS spectra confirm the structure given.

The Rf value in chloroform is 0.40.

EXAMPLE VI Preparation of (-)-1-acetoxy-3-pentyl-6,6-dimethyI9-acetoxymethyl- 6a,10a-trans-6a,7,10,IOa-tetrahydrodibenzo-(b,d)- pyran (Formula 3) 185 mg of the compound obtained in Example V are heated in a tube sealed under high vacuum to 290C and kept at this temperature for 15 minutes. Distillation of the reaction product at 200C/0.001 mmHg yields 160 mg of a reaction mixture from which the Formula 3 compound (R =methyl, R n-pentyl) is obtained by chromatography on 5 g of Florisil" and elution in a yield of mg.

The Rf value of this compound in chloroform is 0.25. Analytical data as well as IR, MMR and MS spectra confirm the structure given.

EXAMPLE VII Preparation of (-)-1-hydroxy-3-n-pentyl-6,6-dimethyl-9- hydroxymethyl-oa, 10a-trans-6a,7,l0,10a-tetrahydrodibenzo-(b,d)-pyran (Formula 1) I 185 mg of the compound obtained according to Example VI are dissolved in 5 ml of dry ether and the solution is added dropwise to a solution of 35 mg of lithium aluminum hydride in 5 ml of ether. The mixture is refluxed for 2 hours. The excess reagent is decomposed by addition of aqueous sodium sulfate solution. After drying over anhydrous sulfate the ether solution is filtered and the ether evaporated. Chromatography over 6 g of Florisil with benzene/chloroform yields the compound of Formula 1 (R n-pentyl).

Analytical data as well as IR, NMR and MS spectra confirm'the structure given in Formula 1.

The Rf value in chloroform/methanol 97:3 is 0.30. The boiling point is 220C/0.001 mm torr. (a),, 231C (0.21 in chloroform).

EXAMPLE VIII Preparation of (-)-1-acetoxy-3-n-pentyl-6,6,9-trimethyl-6a,lOa-trans- 6a,7,10,l 0a-tetrahydrodibenzo-(b,d)-pyran (Formula Analytical data as well as IR, NMR and MS spectra confirm the structure given.

The Rf value in chloroform/methanol 97:3 is 0.70. The boiling point is 145C/0.00l torr.

EXAMPLE'IX Preparation of (-)-l ,8-dihydroxy-3-n-pentyl-6,6-dimethyl-9- methylidene-oa,l0a-trans-6a,7,10,10a-tetrahydrotlibenzo-(b,d)-pyran (Formulae 5a, 5b)

6.88 g ofthe compound obtained in Example VII and 200 mg of rose bengal are dissolved in ml of equal parts by weight of benzene/methanol 1:1. Gaseous oxygen is bubbled through the solution and the solution is irradiated by means of a conventional high-pressure mercury lamp of the type used for photochemical reactions during 8 hours at room temperature (20-25C). The reaction mixture (containing compounds 8a, 8b) is cooled in ice and treated with a total of 15 g of sodium borohydride added portionwise. After completion of the addition stirring is continued for 12 hours at room temperature. Then, 1 n hydrochloride acid is added until the pH of the solution is 78. Extraction with ether, drying the ether extract with sodium sulfate and evaporation of the solvent yields 7.36 g of a product which is purified by chromatography on 150g of Florisil. Elution with benzene/hexane 1:1 and pure benzene yields a mixture of the enantiomeric secondary alcohols of Formulae 5a, 5b (R =n-pentyl). Pure product yield is 44 The product is the same as that of Example 1V and can be used as described in Examples V, VI and VII.

EXAMPLE X Preparation of (-)-l ,9-dihydroxy-3-n-pentyl-6,6,9-trimethyl-6a-10atrans-6a, l 0, l a-tetrahydrodibenzo-( b,d)-pyran (Formula 6) When the absorbent Florisil remaining in Example 1X after elution of the Formula 5a, 5b compound is further eluted with 3:1 benzene/ether, 2.65 g of tertiary alcohol of Formula 6 compound (R n-pentyl) are obtained.

Analytical data as well as 1R, NMR and MS spectra confirmed the structure given.

The Rf value is 0.16 in chloroform/methanol 97:3. ((1) -76.5 (0.5 in chloroform).

EXAMPLE XI Preparation of (-)-1,9dihydroxy-3-n-pentyl-6,6,9-trimethyl-6a,10atrans-6a.7,8.10,10a-hexahydrodibenzo-(b,d)-pyran (Formula 7).

Ulla-OH ill on 7 6159a, I4

where R, is selected from the group consisting of straight and branched chain alkyl radicals containing from about 10 C-atoms. comprising the steps of (a) heating a compound of the formula 10 where R is selected from the group consisting of hydrogen and alkyl radicals of from 1 to about 5 C-atoms to form a compound of the formula (b) reacting said formula (3) with a deacylationagent, and (c) recovering the formula 1) compound thus obtained.

2. The process as claimed in claim 1, wherein said compound of formula (2) is heated to a temperature in the range of from about 200C to about 300C.

3. The process as claimed in claim 2, wherein said compound of formula (2) is heated to about 290C.

4. The process as claimed in claim 1, wherein R, is the n-pentyl radical.

5. The process as claimed in claim 1, wherein R is the methyl group.

6. A process for preparing a compound of the formula I I m/I-I one pp where R is a protective group, with a peracid to obtain a compound of the formulae reacting the compound (4b) with a base to produce a compound of the formula reacting the compound (12) with an agent capable of removing said R group and forming compounds of the formulae reacting compound (5(1), (511) with an acylating agent to yield compound (2).

7. A process for preparing a compound of the formula where R is selected from the group consisting ofhydrogen and alkyl groups having from 1 to about 5 C-atoms,

and R, is selected from the group consisting of straight and branched chain alkyl radicals having from 1 to about C-atoms, comprising the steps of oxidizing a compound of the formula where R;; is a protective group, by treatment with actinic radiation in the presence of oxygen to obtain compounds of the formulae k/ [H (iLRa I HOO reacting compounds (81)) with a reducing agent to obtain compounds of the formulae reacting compounds (5a), (5b) with an acylating agent to yield compound (2).

8. A compound of the formula 13 14 where R is selected from the group consisting of from 1 to about lOC-atoms. straight and branched chain alkyl radicals containing 11. A compound of the formula from 1 to about 10 C-atoms, with the proviso that R is not the n-pentyl group.

011 9. A compound of the formula 5 f CH3 l 11 on 9\ Hi 10 l H 0R2 I AO/ R1 a 7 15 straight and branched chain alkyl radicals containing from 1 to about 10 C-atoms. where R is selected from the group consisting of 12. A compound of the formula straight and branched chain alkyl radicals containing from 1 to about 10 C-atoms and R is hydrogen.

10. A compound of the formula y ll II on n0 I u on (5b) where R is selected from the group consisting olt straight and branched chain alkyl radicals containing where R is selected from the group consisting of from I to about l0C dwmS straight and branched chain alkyl radicals containing .r. i- -la l l I H t where R is selected from the group consisting of 

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA
 2. The process as claimed in claim 1, wherein said compound of formula (2) is heated to a temperature in the range of from about 200*C to about 300*C.
 3. The process as claimed in claim 2, wherein said compound of formula (2) is heated to about 290*C.
 4. The process as claimed in claim 1, wherein R1 is the n-pentyl radical.
 5. The process as claimed in claim 1, wherein R is the methyl group.
 6. A process for preparing a compound of the formula
 7. A process for preparing a compound of the formula
 8. A compound of the formula
 9. A compound of the formula
 10. A compound of the formula
 11. A compound of the formula
 12. A compound of the formula 